Severe phenotype with cis‐acting heterozygous PMP22 mutations

Abstract

We report on a 20-year-old male with severe Charcot-Marie-Tooth (CMT) disease and a de novo deletion (c.281delG, p.G94AfsX17) on the paternal PMP22 allele harboring c.353C>T (p.T118M). RNA-based sequence analysis confirmed the absence of nonsense-mediated decay and the presence of the mutant transcripts in Epstein-Barr virus-transformed lymphoblastoid cells of our patient. His clinical findings included early onset of polyneuropathy, loss of muscle mass with distal pareses, hammer toes, and progressive scoliosis. There was no neuropsychological alteration. Our results suggest that the deletion c.281delG alone is responsible for the severe CMT phenotype. To the best of our knowledge, this is the second report on a proven paternal origin of a de novo single-base mutation in the PMP22 gene.

Computational Analysis Reveals the Association of Threonine 118 Methionine Mutation in PMP22 Resulting in CMT-1A

“…Finally, we screened T118M as the most deleterious and disease-associated mutation in PMP22 gene (Table 3). This prediction could be endorsed with the noticed experimental data [8, 11–13]. We explored T118M mutation in detail.…”

“…The T118M mutation has also been stated in a family in which the parents had a slight phenotype and carried both a CMT1A duplication and T118M mutation, whereas a younger family member had a more severe disease but carried only the duplication, telling that T118M is a part loss-of-function mutation which can mitigate the effects of the duplication [11]. Later the mutation T118M of the PMP22 gene was seen to be a causative mutation in many CMT1A cases [8, 11–13]. …”

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability

“…(Thr118Met)C5[25–28] PMP22 NM_000304.2c.281delGp. (Gly94Alafs*17)C5[36–38]3HMN PMP22 NM_000304.2c.353C > Tp. (Thr118Met)C5[25–28] REEP1 NM_001164730.1c.…”

Genotype–phenotype characteristics of Vietnamese patients diagnosed with Charcot–Marie–Tooth disease

“…To date, point mutations on PMP22 related to CMT1E have been documented including, 44 missense mutations, 14 deletions, two insertions, one reciprocal translocation, and several splice-site and single base substitutions in noncoding region 3′ UTR (Li et al, 2013). Three cases with the same 1-bp deletion in codon 94 of PMP22 have been published (Boerkoel et al, 2002;Ionasescu et al, 1997;Niedrist et al, 2009). Our proband diagnosed with a hereditary motor and sensory neuropathy at an early age shared comparable severe clinical phenotypes with the reported cases, although spine deformity and deafness…”